The induction and development of angiogenesis is a pre-requisite for the development of a primary tumour, and for any subsequent metastases.
Angiogenesis is a dynamic process closely linked with the proliferation of cancer cells, because it is the latter that are chiefly responsible for the production and release of angiogenic factors, such as cytokines and other trophic factors. An increase in the vascularisation of a primary tumour can cause an increase in the number of cancer cells that enter into the circulation and give rise to new metastases.
Recent studies have demonstrated that an increase in the density of microvessels in an area affected by neoplasia indicates new tumour growth.
It is therefore clinically important to suppress angiogenesis to inhibit its development, if possible. Indeed, by associating anti-angiogenic therapy with “classic” anticancer therapy with drugs and/or radiation, with or without surgical removal of the tumour, it is possible to halt the proliferation of cancer cells, thus preventing the invasion of further tissues by said cells, and the consequent development of new metastases (Skobe H. et al., Nature Medicine, 1222-1227 (1997)).
In histological assessment of the onset of the angiogenic process associated with a cancerous growth, it is important to look for markers of the tumour's vascular system, for example with antibodies that differentiate the endothelial cells from the cancerous ones. For example, the anti-CD3 antibody is specific for marking the endothelial cells and therefore enables their identification in the angiogenic process associated with the development of new metastases. Its use has proved essential in assessing the level of microvessel development associated with neoplasia. Indeed, thanks to antibody marking, it is possible to visualise and count the number of interconnections of the vessels within the cancerous tissue to understand and quantify the angiogenic process, relating it to any new developments in the neoplasia (thereby deciding if/how much/how to associate a therapy that modulates or inhibits angiogenesis with an established/classic anticancer therapy.
One such therapy consists in administering drugs that act by blocking the receptors of the trophic factors (PGDF, bFGF, VEGF) that are also angiogenic factors.
Preclinical results ‘in vivo’ have shown that said drugs prove important in inhibiting tumour growth but they do not determine regression of the tumour itself: on the strength of these major experimental data, the drugs have been introduced in numerous clinical trials.
However, an anti-angiogenic clinical therapy that provides for a generally oral pharmacological administration in chronic form may have many toxic side effects, because angiogenesis is not only associated with pathological disorders but also physiological processes such as tissue reproduction and repair (“Cancer: Principle Practice of Oncology” V. De Vita, S. Hellmann and S. Rosenberg, 6th Edition).
It is therefore of strategic importance to associate classic anticancer therapy with an anti-angiogenic therapy “in situ”, and this is the subject of the present invention.
Hyaluronic acid is one of the chief components of the extracellular matrix of the connective tissue, and there are numerous scientific publications concerning its role in various processes, both physiological and pathological, such as the formation of granulation tissue, chemotaxis in the inflammatory process, cell differentiation for various cell types. Other studies concern its role within the family of “substrate adhesion molecules”.
Hyaluronic acid has been used for the above indications:                as a differentiating agent in therapy for acute myeloid leukaemia (Charrad R. S. et al., Nature Medicine 5, 669-676 (1999));        as a vehicle for drugs such as steroids or NSAIDs, antibiotics and anti-neoplastic agents, because of the abundant expression of its receptor (CD44) in cancer cells; (Freemantle, C. et al., Int. J. Tiss. Reac. XVIII (4) 157-166 (1995); Coradini, D. et al., Int. J. Cancer 5, 411-416 (1999));        in preclinical studies on the inhibition of lung metastasis, because of its capacity for inhibiting the adhesion of cancer cells to the vascular endothelium (Karasaza K. et al., Clinical & Experimental Metastasis 15, 83-93 (1997));        as a means of controlling adhesion to the substrate with subsequent proliferation of cells (possibly also cancer cells) permanently “in situ” after surgical removal of tissues (including tumours) (U.S. Pat. No. 5,627,162).        
Experimental observations “in vivo” have, however, revealed that hyaluronic acid may have a chemotaxic activity on cancer cells within the granulation tissue that forms after removal of cutaneous metastasis of melanoma (Salmon-Ehr, V. et al., Ann. Dermatol. Venereol, 123, 194-195 (1996)). Moreover, numerous pre-clinical studies have demonstrated that hyaluronic acid enhances cancer cell migration, thereby favouring metastasis, as it is known that the degradation products of hyaluronic acid, that is, oligosaccharides constituted by 10 and 20 oligomers, are strong inducers of the angiogenic process (Hayen et al., J. Cell. Sci. 112, 2241-2251 (1999); Slevin, M. et al., Lab. Invest. 78 (8), 987-1003 (1998)).
Moreover, biomaterials based on hyaluronic acid and/or the derivatives thereof have never been used as an anti-angiogenic therapy, neither have any other biodegradable and/or non-biodegradable biopolymers ever been used in anticancer therapies.
Absolutely innovative, therefore, is the use of biomaterials based on hyaluronic acid derivatives such as Hyaff® (EP 0 216 453 B1) or ACPs (EP 0 341 745 B1) in the form of non-woven felts for instance (EP0 618 817 B1) or as three-dimensional structures (WO 99/61080), possibly in association with various biomaterials (e.g. natural ones such as collagen, cellulose, polysaccharides, chitin, chitosan, pectin, agar, gellan and alginic acid, synthetic ones such as polylactic acid (PLA), polyglycolic acid (PGA), polyurethanes and polysulphonic resins, or semisynthetic ones such as collagen cross-linked with aldehyde, diamine and gellan) as a therapy to suppress and/or inhibit the angiogenic process that enhances and determines tumour metastasis.